Transcript the slides - ARV

Comparison of INSTI vs INSTI
 QDMRK
 SPRING-2
SPRING-2 Study: DTG QD + 2 NRTI vs RAL BID
+ 2 NRTI
 Design
Randomisation*
1:1
Double-blind
> 18 years
ARV-naïve
HIV RNA > 1,000 c/mL
Any CD4 cell count
No primary resistance
in RT or protease
N = 411
N = 411
W48
W96
DTG 50 mg QD + RAL placebo
+ 2 NRTI**
RAL 400 mg BID + DTG placebo
+ 2 NRTI**
*Randomisation (DTG vs RAL) was stratified by HIV RNA (< or > 100,000 c/mL) at screening and NRTI backbone
**NRTI backbone (TDF/FTC or ABC/3TC if exclusion of the HLA-B*5701 allele) selected by investigator
 Objective
– Non inferiority of DTG at W48: % HIV RNA < 50 c/mL by intention to treat,
snapshot analysis (1-sided significance level of 2.5%, lower margin of the 95%
CI for the difference = -10%, 90% power)
SPRING-2
Raffi F. Lancet 2013;381:735-43
SPRING-2 Study: DTG QD + 2 NRTI vs RAL BID
+ 2 NRTI
Baseline characteristics and patient disposition
DTG + 2 NRTI
N = 411
RAL + 2 NRTI
N = 411
37
35
Female
15%
14%
HIV RNA (log10 c/mL), median
4.52
4.58
HIV RNA > 100,000 c/mL
28%
28%
CD4 cell count (/mm3), median
359
362
CD4 < 200 per mm3
13%
12%
Hepatitis B / hepatitis C coinfection
2% / 10%
2% / 9%
Dual NRTI on day 1 : TDF/FTC / ABC/3TC
59% / 41%
60% / 40%
Discontinuation by W48
47 (11.4%)
56 (13.6%)
N = 16
N = 24
N=8/N=2
N=6/N =1
N=4
N=7
N = 13 / N = 4
N = 11 / N = 7
62 (15%)
79 (19%)
Median age, years
For virologic failure
For adverse event / For liver stopping criteria
Lost to follow-up
Protocol deviation / Withdrew consent
Discontinuation by W96
SPRING-2
Raffi F. Lancet 2013;381:735-43 ; Raffi F. Lancet Infect Dis 2013; 13:927-35
SPRING-2 Study: DTG QD + 2 NRTI vs RAL BID
+ 2 NRTI
Response to treatment at week 48
HIV RNA < 50 c/mL
%
100
DTG + 2NRTI
RAL + 2 NRTI
Primary analysis
89.9
87.8
88.4
Non-inferiority was also supported by
Kaplan-Meier estimates of the
proportion of patients without virological
failure by week 48
85.4
75
50
The number of patients who achieved
the primary endpoint was similar
between subgroups in analyses that
combined high and low HIV RNA strata
and backbone NRTI
25
0
SPRING-2
ITT, snapshot
Per protocol
Adjusted difference
(95% CI) =
2.5% (- 2.2 ; 7.1)
Adjusted difference
(95% CI) =
= 1.6% (- 2.7 ; 5.9)
Median CD4/mm3 increase at W48 :
+ 230 in both groups
Raffi F. Lancet 2013;381:735-43
SPRING-2 Study: DTG QD + 2 NRTI vs RAL BID
+ 2 NRTI
HIV-1 RNA < 50 c/mL at week 48 by stratification factors
DTG 50 mg QD
N = 411
RAL 400 mg BID
N = 411
Difference in %
(95% CI)
DTG – RAL
Number of Responders/Number Assessed
Baseline Plasma HIV-1 RNA
≤ 100,000 c/mL
267 / 297 (90%)
264 / 295 (89%)
0.4 (-4.5, 5.3)
>100,000 c/mL
94 / 114 (82%)
87 / 116 (75%)
7.5 (-3.1, 18.0)
P = 0.236*
Background Dual NRTI
ABC/3TC
145 / 169 (86%)
142 / 164 (87%)
-0.8 (-8.2, 6.6)
TDF/FTC
216 / 242 (89%)
209 / 247 (85%)
4.6 (-1.3, 10.6)
P = 0.264*
* Test for homogeneity
SPRING-2
Raffi F. Lancet 2013;381:735-43
SPRING-2 Study: DTG QD + 2 NRTI vs RAL BID
+ 2 NRTI
Response to treatment at week 96
HIV RNA < 50 c/mL at week 96
DTG + 2 NRTI
RAL + 2 NRTI
%
%
ITT snapshot, by baseline stratification factors
100
100
83.5
80.8
76.4
82
78
80.4
82
86
77
75
75
74
76
63
50
50
25
25
0
0
ITT, snapshot
Per protocol
Adjusted difference Adjusted difference
(95% CI) =
(95% CI) =
4.5 % (- 1.1 ; 10.0) 3.2 % (- 2.1 ; 8.6)
SPRING-2
HIV-1 RNA (c/mL)
> 100,000
≤ 100,000
NRTI backbone
TDF/FTC
ABC/3TC
Raffi F. Lancet Infect Dis 2013;13:927-35
SPRING-2 Study: DTG QD + 2 NRTI vs RAL BID
+ 2 NRTI
 Virologic non-responders (ITT, snapshot) at week 96 by baseline
stratification factors
DTG 50 mg QD
N = 411
RAL 400 mg QD
N = 411
Baseline HIV-1 RNA < 100,000 c/mL
10/297 (3)
17/295 (6)
Baseline HIV-1 RNA > 100,000 c/mL
12/114 (11)
26/116 (22)
ABC/3TC
10/169 (6)
16/164 (10)
TDF/FTC
12/242 (5)
27/247 (11)
ABC/3TC TDF/FTC ABC/3TC TDF/FTC
(N = 169) (N = 242) (N = 164) (N = 247)
Baseline HIV-1 RNA < 100,000 c/mL
6/132 (5)
4/165 (2)
8/125 (6)
9/170 (5)
Baseline HIV-1 RNA > 100,000 c/mL
4/37 (11)
8/77 (10)
8/39 (21)
18/77 (23)
SPRING-2
Raffi F. Lancet Infect Dis 2013;13:927-35
SPRING-2 Study: DTG QD + 2 NRTI vs RAL BID
+ 2 NRTI
 Virologic failure definition
– 2 consecutive plasma HIV-1 RNA > 50 c/mL, on or after W24
 Criteria for resistance testing
– All patients with protocol defined virologic failure (PDVF)
– Genotype of RT and integrase on baseline and suspected virologic failure samples
Resistance data at PDVF
DTG + 2 NRTI , N = 411
PDVF
Integrase genotype results at baseline
and time of PDVF
Emergent integrase-resistance mutations
Reverse transcriptase genotype results
at baseline and time of PDVF
Emergent NRTI-resistance mutations
RAL + 2 NRTI, N = 411
D0-W48
W48-W96
D0-W48
W48-W96
20 (4.9%)
2
28 (6.8%)
1
8
2
18
1
0
0
1*
0
12
2
19
1
0
0
4*
0
* 1 patient with INSTI mutations (T97T/A, E138E/D, V151V/I, N155H) and NRTI mutations (A62A/V, K65K/R, K70K/E, M184V),
1 patient with M184M/I, 1 with M184M/V, 1 with A62A/V
SPRING-2
Raffi F. Lancet 2013;381:735-43 ; Raffi F. Lancet Infect Dis 2013;13:927-35
SPRING-2 Study: DTG QD + 2 NRTI vs RAL BID
+ 2 NRTI
 Adverse events at week 48
Any adverse event
AE in > 5% of subjects in either group
Nausea
Headache
Nasopharyngitis
Diarrhoea
Upper respiratory tract infection
Dizziness
Pyrexia
Fatigue
Insomnia
Bronchitis
Depression
Pharyngitis
Influenza
Asthenia
Syphilis
SPRING-2
DTG + 2 NRTI
RAL + 2 NRTI
82%
83%
14%
12%
11%
11%
6%
6%
5%
5%
5%
5%
5%
5%
3%
3%
2%
13%
12%
12%
11%
6%
6%
5%
4%
4%
4%
3%
3%
5%
5%
5%
Raffi F. Lancet 2013;381:735-43
SPRING-2 Study: DTG QD + 2 NRTI vs RAL BID
+ 2 NRTI
 Graded laboratory toxic effects : rates similar between groups
 Serious adverse events at week 48
DTG + 2 NRTI
RAL + 2 NRTI
Any serious adverse event
N = 29 (7.1%)
N = 31 (7.3%)
SAE related to study drug
N=3
N=5
0
N=1
Arrhythmia
N=1
0
Convulsion
0
N = 2*
Diarrhoea
0
N=1
Hepatitis
N=1
0
Hypersensitivity
N=1
N=1
0
N = 1*
Aphasia
CPK increased
* 1 patient with elevated CPK + convulsion
 Safety between W48 and W96
– Adverse events leading to discontinuation : 0 for DTG vs 3 for RAL
– No serious adverse events related to study drugs
SPRING-2
Raffi F. Lancet 2013;381:735-43 ; Raffi F. Lancet Infect Dis 2013; 13:927-35
SPRING-2 Study: DTG QD + 2 NRTI vs RAL BID
+ 2 NRTI
 Mean change in serum creatinine concentration (µmol/L) from baseline
40
30
DTG 50 mg QD
RAL 400 mg BID
20
12.3
14.6
4.7
8.2
10
0
-10
-20
Baseline
4 8 12 16
24
32
40
48
60
72
84
96
 Mean change in estimated creatinine clearance (CG formula) at W96 :
– - 19.6 mL/min for DTG vs – 9.3 mL/min for RAL
 No discontinuations due to renal events through 96 weeks
SPRING-2
Raffi F. Lancet Infect Dis 2013;13:927-35
SPRING-2 Study: DTG QD + 2 NRTI vs RAL BID
+ 2 NRTI
 Conclusion
– DTG 50 mg QD was virologically non-inferior to RAL BID,
(both + 2 NRTIs) over 48 and 96 weeks
– No INSTI mutations were detected through 96 weeks with DTG
– DTG was similar to RAL in terms of safety and tolerability
– Low occurrence of adverse events leading to discontinuation :
2% in each group
– Between W48 and W96 : few new virologic failures and few
discontinuations for adverse events
– No discontinuation due to renal events through 96 weeks
– Mean increases in creatinine with accompanying decreases in
estimated glomerular filtration rate
• occurred in both study groups by week 4
• generally stabilised and did not change up to week 96
SPRING-2
Raffi F. Lancet 2013;381:735-43 ; Raffi F. Lancet Infect Dis 2013;13:927-35